U.S. patent application number 12/200748 was filed with the patent office on 2010-03-04 for nanovitamin synthesis.
Invention is credited to Dong June Ahn.
Application Number | 20100055187 12/200748 |
Document ID | / |
Family ID | 41725795 |
Filed Date | 2010-03-04 |
United States Patent
Application |
20100055187 |
Kind Code |
A1 |
Ahn; Dong June |
March 4, 2010 |
NANOVITAMIN SYNTHESIS
Abstract
Stable nanoparticulate vitamin compositions are prepared from
agglomerated or larger sized vitamin particles of at least one
vitamin compound by breaking down and/or solubilizing the
agglomerated or larger sized vitamin particles and associating the
particles with a surface modifying agent.
Inventors: |
Ahn; Dong June; (Seoul,
KR) |
Correspondence
Address: |
EDWARDS ANGELL PALMER & DODGE LLP
P.O. BOX 55874
BOSTON
MA
02205
US
|
Family ID: |
41725795 |
Appl. No.: |
12/200748 |
Filed: |
August 28, 2008 |
Current U.S.
Class: |
424/489 |
Current CPC
Class: |
A61K 9/145 20130101 |
Class at
Publication: |
424/489 |
International
Class: |
A61K 9/14 20060101
A61K009/14 |
Claims
1. A method of preparing a stable nanoparticulate vitamin
composition, comprising: providing a precursor mixture that
includes: particles of at least one vitamin compound having a first
size; at least one solvent in which the at least one vitamin
compound has a solubility of less than 10 mg/ml; and molecules of
at least one surface modifying agent; and treating the precursor
mixture to produce smaller sized vitamin particles having a second
size in a range from about 1 nm to about 2000 nm, wherein the
molecules of the at least one surface modifying agent stably
associate with and stabilize the smaller sized vitamin
particles.
2. A method as recited in claim 1, wherein the particles of the at
least one vitamin compound are provided as a powder or slurry of
individual particles or agglomerates, wherein the first size is in
a range of about 100 .mu.m to about 2 .mu.m.
3. A method as recited in claim 1, further comprising selecting at
least one water-partitionable vitamin compound or at least one
lipid-partitionable vitamin compound.
4. A method as recited in claim 3, wherein the at least one
water-partitionable vitamin is selected from the group consisting
of vitamin B.sub.1, vitamin B.sub.2, vitamin B.sub.3, vitamin
B.sub.5, vitamin B.sub.6, vitamin B.sub.7, vitamin B.sub.9, vitamin
B.sub.12, or vitamin C, and combinations thereof.
5. A method as recited in claim 3, wherein the at least one
lipid-partitionable vitamin is selected from the group consisting
of vitamin A, vitamin D, vitamin E, or vitamin K, and combinations
thereof.
6. A method as recited in claim 1, wherein the solvent is selected
from the group consisting of water, aqueous salt solutions,
methanol, ethanol, propanol, butanol, glycerol, propylene glycol,
propylene glycol ethers, dimethyl formamide, N-methyl pyrrolidone,
acetone, diethyl ether, chloroform, benzene, tetrahydrofuran,
hexanes, ethyl acetate, methyl methacrylate, toluene, phenyl
ethers, vegetable oil, and combinations thereof.
7. A method as recited in claim 1, wherein the surface modifying
agent includes at least one of an organic acid, a long-chain amine,
a surfactant, an anionic surface stabilizer, a cationic surface
stabilizer, a zwitterionic surface stabilizer, or an ionic surface
stabilizer, and optionally includes one or more long-chain
alcohols.
8. A method as recited in claim 7, wherein the organic acid is a
fatty acid chosen from the group consisting of butanoic acid,
pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid,
nonanoic acid, decanoic acid, undecanoic acid, dodecanoic acid,
tridecanoic acid, tetradecanoic acid, pentadecanoic acid,
hexadecanoic acid, heptadecanoic acid, octadecanoic acid,
nonadecanoic acid, eicosanoic acid, uncosanoic acid, docosanoic
acid, tricosanoic acid, tetracosanoic acid, undecylenic acid,
myristoleic acid, palmitoleic acid, oleic acid, linoleic acid,
alpha-linolenic acid, arachidonic acid, eicosapentaenoic acid,
erucic acid, docosahexaenoic acid, and metals salts thereof.
9. A method as recited in claim 7, wherein the surface modifying
agent includes at least one long-chain amine with a chain length of
at least 6 carbon atoms.
10. A method as recited in claim 7, wherein the surfactant is
selected from the group consisting of octylphenol ethoxylates,
phosphonic acids, phosphinic acids, sulfonic acids, polyethylene
glycol monoalkyl ethers, and combinations thereof.
11. A method as recited in claim 1, wherein the treating further
comprises: transferring the precursor mixture to a microfluidizer
having an interaction chamber capable of producing one or more of
shear, impact, cavitation, or attrition forces; and subjecting the
precursor mixture to said forces at a temperature not exceeding
60.degree. C. and a fluid pressure of from about 3,000 to about
30,000 psi by passing the precursor mixture through said
interaction chamber to obtain vitamin particles having an effective
average particle size in a range from about 1 nm to about 2000
nm.
12. A method as recited in claim 1, wherein the treating further
comprises: sonicating the precursor mixture a temperature not
exceeding 60.degree. C., for a time in a range from about 5 minutes
to about 2 hours, wherein the sonicating suspends the particles of
the at least one vitamin in the solvent allows the surface
modifying agent to associate with the particles of the at least one
vitamin, and wherein the sonicating disrupts or breaks down the
particles of the at least one vitamin into smaller vitamin
particles having a second size in a range from about 1 nm to about
2000 nm.
13. A method as recited in claim 1, wherein vitamin particles of
the stable, nanoparticulate vitamin composition are substantially
sphere-shaped and/or substantially rod-shaped.
14. A method of preparing a stable nanoparticulate vitamin
composition, comprising: selecting at least one vitamin compound
from a group consisting of water-partitionable vitamins or a group
consisting of lipid-partitionable vitamins; providing a precursor
mixture that includes: particles of at least one vitamin compound
having a first size in a range of about 100 .mu.m to about 2 .mu.m,
the particles being provided as a powder or slurry of individual
particles or agglomerates; at least one solvent in which the at
least one vitamin compound has a solubility of less than 10 mg/ml;
and molecules of at least one surface modifying agent that are
dispersible in the at least one solvent and are capable of stably
bonding to the particles of the at least one vitamin compound; and
breaking down the particles of the at least one vitamin compound in
the precursor mixture to produce the stable nanoparticulate vitamin
composition by subjecting the precursor mixture to shear, impact,
cavitation, sonication, and/or attrition forces, wherein the stable
nanoparticulate vitamin composition comprises smaller sized vitamin
particles having a second size in a range from about 1 nm to about
2000 nm, and wherein the molecules of the at least one surface
modifying agent stably associate with and stabilize the smaller
sized vitamin particles.
15. A method as recited in claim 14, wherein the at least one
water-partitionable vitamin is selected from the group consisting
of vitamin B.sub.1, vitamin B.sub.2, vitamin B.sub.3, vitamin
B.sub.5, vitamin B.sub.6, vitamin B.sub.7, vitamin B.sub.9, vitamin
B.sub.12, or vitamin C, and combinations thereof.
16. A method as recited in claim 14, wherein the at least one
lipid-partitionable vitamin is selected from the group consisting
of vitamin A, vitamin D, vitamin E, or vitamin K, and combinations
thereof.
17. A method as recited in claim 14, wherein the solvent is
selected from the group consisting of acetone, diethyl ether,
chloroform, benzene, tetrahydrofuran, hexanes, ethyl acetate,
methyl methacrylate, toluene, phenyl ethers, vegetable oils, and
combinations thereof.
18. A method as recited in claim 14, wherein the solvent is
selected from the group consisting of water, aqueous salt
solutions, methanol, ethanol, propanol, butanol, glycerol,
propylene glycol, or propylene glycol ethers, and combinations
thereof.
19. A method as recited in claim 14, wherein the surface modifying
agent includes at least one of an organic acid, a long-chain amine,
a surfactant, an anionic surface stabilizer, a cationic surface
stabilizer, a zwitterionic surface stabilizer, or an ionic surface
stabilizer, and optionally includes one or more long-chain
alcohols.
20. A stable nanoparticulate vitamin composition, comprising:
nano-particles of at least one vitamin compound having a size in a
range from about 1 nm to about 2000 nm; and molecules of at least
one stabilizing agent associated with the nano-particles.
21. A stable nanoparticulate vitamin composition as recited in
claim 20, wherein the nano-particles of the stable nanoparticulate
vitamin composition have a size in a range from about 50 nm to
about 1500 nm.
22. A stable nanoparticulate vitamin composition as recited in
claim 20, wherein the nano-particles of the stable nanoparticulate
vitamin composition have a size in a range from about 100 nm to
about 1000 nm.
23. A stable nanoparticulate vitamin composition as recited in
claim 20, wherein the nano-particles of at least one vitamin
compound are selected from a group consisting of
water-partitionable vitamins or a group consisting of
lipid-partitionable vitamins.
24. A stable nanoparticulate vitamin composition as recited in
claim 20, wherein the surface modifying agent includes at least one
of an organic acid, a long-chain amine, a surfactant, an anionic
surface stabilizer, a cationic surface stabilizer, a zwitterionic
surface stabilizer, or an ionic surface stabilizer, and optionally
includes one or more long-chain alcohols.
25. A stable nanoparticulate vitamin composition as recited in
claim 20, further comprising at least one solvent in which the at
least one vitamin compound has a solubility of less than 10 mg/ml,
wherein the solvent is selected from the group consisting of water,
aqueous salt solutions, methanol, ethanol, propanol, butanol,
glycerol, propylene glycol, propylene glycol ethers, dimethyl
formamide, N-methyl pyrrolidone, acetone, diethyl ether,
chloroform, benzene, tetrahydrofuran, hexanes, ethyl acetate,
methyl methacrylate, toluene, phenyl ethers, vegetable oil, and
combinations thereof.
Description
BACKGROUND
[0001] A vitamin is commonly defined as an organic compound
required as a nutrient in small or trace amounts by an organism.
Ingestion of vitamins as part of the diet is typically necessary
because vitamins cannot be synthesized in sufficient quantities by
an organism. Thus, the term is conditional both on the circumstance
and the particular organism. For example, ascorbic acid functions
as vitamin C for some animals but not others, and vitamins D and K
are required in the human diet only in certain circumstances.
[0002] Vitamins are classified by their biological and chemical
activity, not their structure. Thus, each "vitamin" actually refers
to a number of vitamer compounds, which form a set of distinct
chemical compounds that show the biological activity of a
particular vitamin. Each set of chemicals is grouped under an
alphabetized vitamin "generic descriptor" title, such as "vitamin
A," which, for example, includes retinal, retinol, and many
carotenoids. Vitamers are often inter-convertible in the body. The
term vitamin does not include other essential nutrients such as
dietary minerals, essential fatty acids, or essential amino acids,
nor does it encompass the large number of other nutrients that
promote health but are otherwise required less often.
[0003] Vitamins have diverse biochemical functions. Some vitamins
function as hormones (e.g., vitamin D), antioxidants (e.g., vitamin
E), and mediators of cell signaling and regulators of cell and
tissue growth and differentiation (e.g., vitamin A). Many vitamins
(e.g., B complex vitamins) function as precursors for enzyme
cofactor bio-molecules (coenzymes) that help act as catalysts and
substrates in metabolism. When acting as part of a catalyst,
vitamins are bound to enzymes and are called prosthetic groups. For
example, biotin forms part of enzymes involved in making fatty
acids. Vitamins also act as coenzymes to carry chemical groups
between enzymes. For example, folic acid carries various carbon
groups (e.g., methyl, formyl, and methylene) in the cell.
[0004] Until the 1900s, vitamins were obtained solely through food
intake, therefore changes in diet can alter the types and amounts
of vitamins ingested. For example, as the availability of certain
foods changes according to the seasons, dietary patterns change and
the ingestion of vitamins changes. In recent times, vitamins have
been produced chemically and made widely available as inexpensive
pills, allowing supplementation of the dietary intake.
[0005] While the definition of "vitamin" is somewhat fluid, there
are 13 dietary substances that are generally recognized as vitamins
in the human diet. Substances generally accepted to be vitamins and
their corresponding vitamers include, but are not limited to,
vitamin A (retinol, retinal retinoids, and carotenoids), vitamin
B.sub.1 (thimine), vitamin B.sub.2 (riboflavin), Vitamin B.sub.3
(niacin, niacinamide), vitamin B.sub.5 (pantothenic acid), vitamin
B.sub.6 (pyridoxine, pyridoxamine, pyridoxal), vitamin B.sub.7
(biotin), vitamin B.sub.9 (folic acid, folinic acid), vitamin
B.sub.12 (cyanocobalimin, hydroxycobalamin, methylcobalamin),
vitamin C (ascorbic acid), vitamin D (ergocalciferol,
cholecalciferol), vitamin E (tocopherols, tocotrienols), and
vitamin K (phylloquinone, menaquinones).
[0006] Vitamins are classified as either water-partitionable,
meaning that they dissolve easily in water, or lipid-partitionable,
which are typically soluble in most common organic solvents and are
absorbed through the intestinal tract with the help of lipids. In
general, water-partitionable vitamins are readily excreted from the
body, while lipid-partitionable vitamins are retained for a longer
period of time. Water-partitionable vitamins include the B vitamins
(i.e., vitamins B.sub.1, B.sub.2, B.sub.3, B.sub.5, B.sub.6,
B.sub.7, B.sub.9, and B.sub.12) and vitamin C. Lipid-partitionable
vitamins include vitamins A, D, E and K.
BRIEF SUMMARY
[0007] The illustrated embodiments relate to novel stable
nanoparticulate vitamin compositions and methods for manufacturing
the same. The stable nanoparticulate vitamin compositions are
prepared by starting with agglomerated or larger sized vitamin
particles of at least one vitamin compound and suspending them in
at least one solvent in the presence of at least one surface
modifying agent to form a slurry. The at least one solvent is
typically selected such that the at least one vitamin compound is
practically insoluble therein. Stable nanoparticulate vitamin
compositions are formed by breaking down and/or solubilizing the
agglomerated or larger sized vitamin particles and associating the
particles with the surface modifying agent.
[0008] The illustrated embodiments are based partly on the
discovery that vitamin particles having a small effective particle
size can be prepared by breaking down larger vitamin particles in
the presence of a solvent in which the vitamin particles are not
soluble in conjunction with a surface modifier. Such particles are
stable and do not appreciably flocculate or agglomerate due to
interparticle attractive forces and can be formulated into vitamin
supplement compositions exhibiting unexpectedly high
bioavailability. Their greater bioavailability means, for example,
that nanoparticulate vitamin compositions can be given in smaller
doses with less of the vitamins passing through the body
unabsorbed.
[0009] In one embodiment, a method of preparing a stable
nanoparticulate vitamin composition is described. In one
embodiment, the method includes providing a precursor mixture that
includes particles of the at least one vitamin compound, at least
one solvent in which the at least one vitamin compound has a
solubility of less than 10 mg/ml, and molecules of at one surface
modifying agent; and treating the precursor mixture to produce
smaller sized vitamin particles, wherein the molecules of the at
least one surface modifying agent stably associate with and
stabilize the smaller sized vitamin particles.
[0010] In one embodiment, the vitamin particles in the precursor
mixture are provided as a powder or slurry of individual particles
or agglomerates having a size in a range of about 100 .mu.m to
about 2 .mu.m, or about 75 .mu.m to about 3 .mu.m, or about 50
.mu.m to about 4 .mu.m.
[0011] In one embodiment, the treating step of the method described
above further includes transferring the precursor mixture to a
microfluidizer having an interaction chamber capable of producing
shear, impact, cavitation, and attrition forces; and subjecting the
precursor mixture to said forces at a temperature not exceeding
40.degree. C. and a fluid pressure of from about 3,000 to about
30,000 psi by passing the precursor mixture through said
interaction chamber to obtain vitamin particles having an effective
average particle size in a range from about 1 nm to about 2000 nm.
One will appreciate that it may take multiple passes through the
microfluidizer in order to obtain vitamin particles having the
desired size.
[0012] In another embodiment, the treating step of the method
described above further includes sonicating the precursor mixture a
temperature not exceeding 40.degree. C., for a time in a range from
about 5 minutes to about 2 hours, wherein the sonicating suspends
the particles of the at least one vitamin in the solvent, allows
the surface modifying agent to associate with the particles of the
at least one vitamin, and disrupts or breaks down the particles of
the at least one vitamin into smaller vitamin particles having a
second size in a desired size range.
[0013] The particles obtained following the microfluidizer
treatment or the sonication treatment are typically substantially
sphere-shaped and/or substantially rod-shaped.
[0014] In a broad range, the vitamin particles in the stable
nanoparticulate vitamin composition have a size in a range from
about 1 nm to about 2000 nm. In a narrower range, the vitamin
particles in the stable nanoparticulate vitamin composition have a
size in a range from about 50 nm to about 1500 nm. In a still
narrower range, the vitamin particles in the stable nanoparticulate
vitamin composition have a size in a range from about 100 nm to
about 1000 nm.
[0015] In one embodiment, the method further includes selecting at
least one water-partitionable vitamin compound or at least one
lipid-partitionable vitamin compound. Water-partitionable vitamin
compounds may be chosen from the group consisting of vitamin B1,
vitamin B2, vitamin B3, vitamin B5, vitamin B.sub.6, vitamin B7,
vitamin B9, vitamin B12, or vitamin C, and combinations thereof.
Lipid-partitionable vitamin compounds may be chosen from the group
consisting of vitamin A, vitamin D, vitamin E, or vitamin K, and
combinations thereof.
[0016] In one embodiment, the solvent is selected from the group
consisting of water, aqueous salt solutions, methanol, ethanol,
propanol, butanol, glycerol, propylene glycol, propylene glycol
ethers, dimethyl formamide, N-methyl pyrrolidone, acetone, diethyl
ether, chloroform, benzene, tetrahydrofuran, hexanes, ethyl
acetate, methyl methacrylate, toluene, phenyl ethers, vegetable
oil, and combinations thereof.
[0017] In one embodiment the solvent may be selected for
compatibility with water-partitionable vitamin compounds or
lipid-partitionable vitamin compounds. That is, the solvent may be
selected such that the at least one vitamin compound has a
solubility of less than 10 mg/ml in the selected solvent. Suitable
examples of solvents in which water-partitionable vitamin compounds
have a solubility of less than 10 mg/ml include, but are not
limited to, acetone, diethyl ether, chloroform, benzene,
tetrahydrofuran, hexanes, ethyl acetate, methyl methacrylate,
toluene, phenyl ethers, vegetable oils (e.g., safflower oil or rape
seed oil), and combinations thereof. Suitable examples of solvents
in which lipid-partitionable vitamin compounds have a solubility of
less than 10 mg/ml include, but are not limited to, water, aqueous
salt solutions, methanol, ethanol, propanol, butanol, glycerol,
propylene glycol, or propylene glycol ethers, and combinations
thereof.
[0018] Suitable examples of surface modifying agents include, but
are not limited to, at least one of an organic acid, a long-chain
amine, a surfactant, an anionic surface stabilizer, a cationic
surface stabilizer, a zwitterionic surface stabilizer, or an ionic
surface stabilizer, and optionally includes one or more long-chain
alcohols.
[0019] In one embodiment, a stable nanoparticulate vitamin
composition is described. The stable nanoparticulate vitamin
composition includes nano-particles of at least one vitamin
compound having a size in a range from about 1 nm to about 2000 nm
and molecules of at least one stabilizing agent associated with the
nano-particles.
[0020] In one embodiment, the nano-particles of at least one
vitamin compound are selected from a group consisting of
water-partitionable vitamins or a group consisting of
lipid-partitionable vitamins.
[0021] In one embodiment, the stable nanoparticulate vitamin
composition further includes at least one solvent in which the at
least one vitamin compound has a solubility of less than 10 mg/ml.
Suitable examples of solvents include, but are not limited to,
water, aqueous salt solutions, methanol, ethanol, propanol,
butanol, glycerol, propylene glycol, propylene glycol ethers,
dimethyl formamide, N-methyl pyrrolidone, acetone, diethyl ether,
chloroform, benzene, tetrahydrofuran, hexanes, ethyl acetate,
methyl methacrylate, toluene, phenyl ethers, vegetable oil, and
combinations thereof.
[0022] These and other objects and features of nanoparticulate
vitamin compositions will become more fully apparent from the
following description and appended claims, or may be learned by the
practice of the claims as set forth hereinafter. The foregoing
summary is illustrative only and is not intended to be in any way
limiting.
DETAILED DESCRIPTION
[0023] The illustrative embodiments described in the detailed
description and claims are not meant to be limiting. Other
embodiments may be utilized, and other changes may be made, without
departing from the spirit or scope of the subject matter presented
here.
I. Introduction
[0024] The illustrated embodiments relate to novel stable
nanoparticulate vitamin compositions and methods for manufacturing
the same. The stable nanoparticulate vitamin compositions are
prepared by starting with agglomerated or larger sized vitamin
particles of at least one vitamin compound and suspending them in
at least one solvent in the presence of at least one surface
modifying agent to form a slurry. The at least one solvent is
typically selected such that the at least one vitamin compound is
practically insoluble therein. Stable nanoparticulate vitamin
compositions are formed by breaking down the agglomerated or larger
sized vitamin particles and associating the particles with the
surface modifying agent.
[0025] The illustrated embodiments are based partly on the
discovery that vitamin particles having a small effective particle
size can be prepared by breaking down larger vitamin particles in
the presence of a solvent in which the vitamin particles are not
soluble in conjunction with a surface modifier. Such particles are
stable and do not appreciably flocculate or agglomerate due to
interparticle attractive forces and can be formulated into vitamin
supplement compositions exhibiting unexpectedly high
bioavailability. For example, their greater bioavailability means
that nanoparticulate vitamin compositions can be given in smaller
doses with less of the vitamins passing through the body
unabsorbed.
[0026] As used herein, the term "nanoparticulate compositions"
refers to stabilized nano-scale particles of a therapeutic or
diagnostic agent having a coating of a stabilizing surface
modifying agent. In some instances, "nanoparticulate compositions"
include a solvent that suspends the stabilized particles.
[0027] As used herein, the term "vitamin particles" refers to
solid, crystalline phase particles of various vitamin vitamer
compounds, such as but not limited to, vitamin B.sub.12, which is
typically provided as cyanocobalimin, hydroxycobalamin, or
methylcobalamin.
[0028] As used herein, the term "precursor mixture" refers to a
mixture of compounds used to make a stable nanoparticulate vitamin
composition. In a minimal sense, the precursor mixture includes a
plurality of vitamin particles, at least one solvent, and at least
on stabilizing compound. The vitamin particles may be provided as a
powder or a slurry.
[0029] As used herein, the term "stable" or "stably suspended" when
used in the context of a stable nanoparticulate vitamin composition
refers to a system in which particles of between 1 nm and 2000 nm
are suspended or dispersed in a continuous phase of a different
composition (i.e., a solvent) such that the stabilized
nanoparticles do not appreciably fall out of suspension and/or
agglomerate over a relatively long period of time (e.g., weeks or
months).
[0030] As used herein, the "surface modifying agent" refers to a
compound or mixture of compounds that are compatible with a given
solvent and that associate with the surface of vitamin particles to
prevent coagulation or agglomeration of the particles in stable
suspension.
[0031] As used herein, the term "nano-scale" or "nano-sized" means
a size between about 1 nm and about 2000 nm.
II. Components used to Manufacture Stable Nanoparticulate Vitamin
Compositions
[0032] The following components can be used to carry out methods
for manufacturing stable nanoparticulate vitamin compositions of
vitamin particles according to the illustrated embodiments.
A. Vitamin Compounds
[0033] The vitamin compounds used to prepare the stable
nanoparticulate vitamin compositions according to the illustrated
embodiments are provided as powders of individual particles and/or
agglomerates or as solvent-based slurries of individual particles
and/or agglomerates. Examples of suitable vitamin particles that
can be used in the illustrated embodiments include, but are not
limited to, vitamin A, vitamin B.sub.1, vitamin B.sub.2, vitamin
B.sub.3, vitamin B.sub.5, vitamin B.sub.6 (pyridoxine,
pyridoxamine, pyridoxal), vitamin B.sub.7 (biotin), vitamin B.sub.9
(folic acid, folinic acid), vitamin B.sub.12 (cyanocobalimin,
hydroxycobalamin, methylcobalamin), vitamin C (ascorbic acid),
vitamin D (ergocalciferol, cholecalciferol), vitamin E
(tocopherols, tocotrienols), and vitamin K (phylloquinone,
menaquinones). The vitamin substance can be present in an
essentially pure or crystalline form.
[0034] In a broad range, the vitamin particles in the stable
nanoparticulate vitamin composition have a size in a range from
about 1 nm to about 2000 nm. In a narrower range, the vitamin
particles in the stable nanoparticulate vitamin composition have a
size in a range from about 50 nm to about 1500 nm. In a still
narrower range, the vitamin particles in the stable nanoparticulate
vitamin composition have a size in a range from about 100 nm to
about 1000 nm. In some embodiments, the vitamin particles have a
size in a range from about 1 nm, 5 nm, 10 nm, 50 nm, 100 nm, 250
nm, 500 nm, 750 nm, 1000 nm, or 1500 nm, to about 5 nm, 10 nm, 50
nm, 100 nm, 250 nm, 500 nm, 750 nm, 1000 nm, 1500 nm, or 2000 nm.
In some embodiments, the vitamin particles have a size of about 1
nm, 5 nm, 10 nm, 50 nm, 100 nm, 250 m, 500 nm, 750 nm, 1000 nm,
1500 nm, or 2000 nm.
[0035] Vitamin A is a lipid partitionable vitamin important in
vision and bone growth. Vitamers of vitamin A include, but are not
limited to, retinol, retinal retinoids, and carotenoids. Retinol is
ingested in a precursor form; animal sources (e.g., liver and eggs)
contain retinyl esters, whereas plants (e.g., carrots, spinach)
contain pro-vitamin A carotenoids. Hydrolysis of retinyl esters
results in retinol while pro-vitamin A carotenoids can be cleaved
to produce retinal, which can be reversibly reduced to produce
retinol or it can be irreversibly oxidized to produce retinoic
acid.
[0036] Vitamin B.sub.1 is a water-soluble B-complex vitamin
important for neural function and carbohydrate metabolism. The most
common vitamer of vitamin B.sub.1 is thiamin. It is soluble in
water, methanol, and glycerol and practically insoluble in acetone,
ether, chloroform, and benzene. Thiamin is found in a wide variety
of many foods at low concentrations, with yeast, liver and cereal
grains being the most common
[0037] Vitamin B.sub.2 is a water-soluble B-complex vitamin that is
an important component of the cofactors FAD and FMN required by all
flavoproteins. Vitamin B.sub.2 plays a key role in energy
metabolism, and is required for the metabolism of fats, ketone
bodies, carbohydrates, and proteins. The most common vitamer of
vitamin B.sub.2 is riboflavin. Milk, cheese, leafy green
vegetables, liver, kidneys, legumes such as mature soybeans, yeast,
almonds and some shellfish are good sources of vitamin B.sub.2.
[0038] Vitamin B.sub.3 is a water-soluble B-complex vitamin that is
a precursor for the enzyme co-factors NADH, NAD, NAD+, and NADP,
which play essential metabolic roles in living cells, DNA repair,
and the production of steroid hormones in the adrenal gland. The
most common vitamers of vitamin B.sub.3 include, but are not
limited to, niacin and niacinamide. Most animal- and plant-based
foods are rich sources of vitamin B.sub.3.
[0039] Vitamin B.sub.5 is a water-soluble B-complex vitamin needed
to form coenzyme-A (CoA), and is critical in the metabolism and
synthesis of carbohydrates, proteins, and fats. The most common
vitamer of vitamin B.sub.5 is pantothenic acid. Small quantities of
pantothenic acid are found in nearly every food, with high amounts
in whole-grains, legumes, eggs, and meat.
[0040] Vitamin B.sub.6 is a water-soluble B-complex vitamin that is
the precursor for pyridoxal phosphate (PLP). PLP is a cofactor in
many reactions of amino acid metabolism, including transamination,
deamination, and decarboxylation. PLP also is necessary for the
enzymatic reaction governing the release of glucose from glycogen.
The most common vitamers of vitamin B.sub.6 include, but are not
limited to, pyridoxine, pyridoxamine, pyridoxal. Vitamin B.sub.6 is
widely distributed in foods in both its free and bound forms. Good
sources of vitamin B.sub.6 include meats, whole grain products,
vegetables, and nuts.
[0041] Vitamin B.sub.7 is a water-soluble B-complex vitamin that
acts as a cofactor in the metabolism of fatty acids and leucine,
and in gluconeogenesis. The most common vitamer of vitamin B.sub.7
is biotin. The most important natural sources of biotin in human
nutrition are milk, liver, egg (egg yolk), and some vegetables.
[0042] Vitamin B.sub.9 is a water-soluble B-complex vitamin
necessary for the production and maintenance of new cells. This is
especially important during periods of rapid cell division and
growth such as infancy and pregnancy. Folate is needed to
synthesize DNA bases (most notably thymine, but also purine bases)
needed for DNA replication. The most common vitamers of vitamin
B.sub.9 are folic acid and folinic acid. Leafy vegetables such as
spinach, turnip greens, lettuces, dried beans and peas, fortified
cereal products, sunflower seeds and certain other fruits and
vegetables are rich sources of vitamin B.sub.9.
[0043] Vitamin B.sub.12 is a water-soluble B-complex vitamin that
is important for the normal functioning of the brain and nervous
system, and for the formation of blood. It is normally involved in
the metabolism of every cell of the body, especially affecting DNA
synthesis and regulation, but also fatty acid synthesis and energy
production. The most common vitamers of vitamin B.sub.12 include,
but are not limited to, cyanocobalimin, hydroxycobalamin, and
methylcobalamin. Cyanocobalimin does not generally occur naturally,
but it is the most common vitamer of B.sub.12 in dietary
supplements because it is more air stable than the other vitamers.
Vitamin B.sub.12 is naturally found in meat (especially liver and
shellfish), milk and eggs. Animals, in turn, must obtain it
directly through food or indirectly from bacteria that inhabit the
gut.
[0044] Vitamin C is a water-soluble vitamin that acts as an
antioxidant and is a cofactor in several enzymatic reactions. The
most common vitamer of vitamin C is ascorbic acid or ascorbate ion.
Many plant-based and animal-based foods are rich sources of vitamin
C.
[0045] Vitamin D is a lipid partitionable vitamin that is important
for many bodily functions including regulating calcium and
phosphorus levels in the blood, promoting bone formation, immune
system regulation. The most common vitamers of vitamin D include,
but are not limited to, ergocalciferol and cholecalciferol.
Cholecalciferol is produced in skin exposed to sunlight,
specifically ultraviolet B radiation. Many foods are rich sources
of vitamin D, including supplemented dairy products.
[0046] Vitamin E is a collective name for a set of 8 related
tocopherols and tocotrienols, which are fat-soluble vitamins with
important antioxidant properties. Many foods such as asparagus,
avocado, and fish oils are rich sources of vitamin E.
[0047] Vitamin K denotes a group of lipophilic, hydrophobic
vitamins that are needed for the posttranslational modification of
certain proteins, mostly required for blood coagulation. The most
common vitamers of vitamin K include, but are not limited to,
phylloquinone, menaquinones. Vitamin K is found leafy green
vegetables, such as spinach and kale, cabbage, cauliflower,
broccoli, brussels sprouts, and some fruits, such as avocado and
kiwifruit.
B. Solvents
[0048] The solvents used to prepare the stable nanoparticulate
vitamin compositions provide a continuous phase for dispersing
vitamin particles of the precursor mixture and/or dispersing the
vitamin particles of the stable nanoparticulate vitamin
compositions. The solvent serves as a carrier for the vitamin
particles and the surface modifying agent. Various solvents or
mixtures of solvents can be used, including but not limited to,
water and organic solvents.
[0049] The vitamin substance is typically poorly soluble and
dispersible in at least one liquid solvent. By "poorly soluble" it
is meant that the vitamin substance has a solubility in the liquid
dispersion medium, e.g., water, of less than about 10 mg/ml, or
less than about 1 mg/ml.
[0050] The choice of solvent is at least partly a function of
vitamin substance or substances. Vitamins are typically classified
as either water-partitionable, meaning that they dissolve easily in
water, or lipid-partitionable, meaning that they dissolve easily in
most common organic solvents and are absorbed through the
intestinal tract with the help of lipids. Water-partitionable
vitamins include, but are not limited to, the B complex vitamins
(i.e., vitamins B.sub.1, B.sub.2, B.sub.3, B.sub.5, B.sub.6,
B.sub.7, B.sub.9, and B.sub.12) and vitamin C. Lipid-partitionable
vitamins include, but are not limited to, vitamins A, D, E and
K.
[0051] Suitable examples of solvents in which water-partitionable
vitamin compounds have a solubility of less than 10 mg/ml include,
but are not limited to, acetone, diethyl ether, chloroform,
benzene, tetrahydrofuran, hexanes, ethyl acetate, methyl
methacrylate, toluene, phenyl ethers, vegetable oils (e.g.,
safflower oil or rape seed oil), and combinations thereof.
[0052] Suitable examples of solvents in which lipid-partitionable
vitamin compounds have a solubility of less than 10 mg/ml include,
but are not limited to, water, aqueous salt solutions, methanol,
ethanol, propanol, butanol, glycerol, propylene glycol, or
propylene glycol ethers, and combinations thereof.
C. Surface Modifying Agents
[0053] The surface modifying agents used to prepare the stable
nanoparticulate vitamin compositions associate with the surface of
vitamin particles to prevent coagulation or agglomeration of the
particles by overcoming the tendency of vitamin particles to
agglomerate due to, e.g., inter-particle attraction. A surface
modifying agent or a mixture of agents is selected such that it is
dispersible or otherwise compatible with a given solvent used to
form the stable nanoparticulate vitamin composition. For example,
the agent or agents can be weakly solublized by the solvent so that
the surface modifying agent is free to bond to and/or associate
with the vitamin particles, but the solvent does not tend to wash
the molecules of surface modifying agent off of the vitamin
particles.
[0054] Molecules of the surface modifying agent molecules are
complexed with the vitamin particles to control formation of the
stable nanoparticulate vitamin composition. The surface modifying
agent is selected to promote the formation of nanoparticulate
vitamin particles that have a desired stability, size, and/or
uniformity. Examples of suitable surface modifying agents include,
but are not limited to, a variety of organic molecules, polymers,
and oligomers. The surface modifying agent can interact and bond
with the vitamin particles dissolved or dispersed within an
appropriate solvent or carrier through various mechanisms,
including ionic bonding, covalent bonding, lone pair electron
bonding, hydrogen bonding, or van der Waals forces. In one
embodiment, useful surface modifiers are believed to include those
which physically adhere to the surface of the vitamin particle but
do not chemically bond to the vitamin.
[0055] Suitable surface modifiers can preferably be selected from
known organic and inorganic pharmaceutical excipients. Such
excipients include, but are not limited to, various polymers, low
molecular weight oligomers, natural products and surfactants.
Preferred surface modifiers include nonionic and anionic
surfactants. Representative examples of excipients include gelatin,
casein, lecithin (phosphatides), gum acacia, cholesterol,
tragacanth, stearic acid, benzalkonium chloride, calcium stearate,
glyceryl monostearate, cetostearyl alcohol, cetomacrogol
emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers,
e.g., macrogol ethers such as cetomacrogol 1000, polyoxyethylene
castor oil derivatives, polyoxyethylene sorbitan fatty acid esters,
e.g., the commercially available Tweens, polyethylene glycols,
polyoxyethylene stearates, colloidol silicon dioxide, phosphates,
sodium dodecylsulfate, carboxymethylcellulose calcium,
carboxymethylcellulose sodium, methylcellulose,
hyclroxyethylcellulose, hydroxypropylcellulose,
hydroxypropylmethycellulose phthalate, noncrystalline cellulose,
magnesium aluminum silicate, triethanolamine, polyvinyl alcohol
(PVA), and polyvinylpyrrolidone (PVP). Most of these excipients are
described in detail in the Handbook of Pharmaceutical Excipients,
published jointly by the American Pharmaceutical Association and
The Pharmaceutical Society of Great Britain, the Pharmaceutical
Press, 1986. The surface modifiers are commercially available
and/or can be prepared by techniques known in the art. Two or more
surface modifiers can be used in combination.
[0056] Other examples of suitable surface modifiers include, but
are not limited to, organic acids, long-chain amines, and
surfactants. In addition to an organic acid, a long-chain amine,
and/or a surfactant, the surface modifying agent may optionally
include at least one long-chain alcohol.
[0057] Examples of suitable organic acids include so-called fatty
acids. A fatty acid is an organic compound with a carboxylic acid
head group and an aliphatic tail. The tail may be either saturated
or unsaturated. A saturated fatty acid has no double bonds in its
tail (i.e., the tail is fully saturated with hydrogen). An
unsaturated fatty acid has at least one double bond in its tail
(i.e., the tail is not fully saturated with hydrogen).
[0058] Examples of suitable saturated fatty acids include, but are
not limited to, butanoic acid, pentanoic acid, hexanoic acid,
heptanoic acid, octanoic acid, nonanoic acid, decanoic acid,
undecanoic acid, dodecanoic acid, tridecanoic acid, tetradecanoic
acid, pentadecanoic acid, hexadecanoic acid, heptadecanoic acid,
octadecanoic acid, nonadecanoic acid, eicosanoic acid, uncosanoic
acid, docosanoic acid, tricosanoic acid, and tetracosanoic acid.
This series of fatty acids have tail lengths that range from four
carbons to 24 carbons. In some embodiments, metal salts of the
fatty acids may be used in lieu of or in addition to the carboxylic
acid form.
[0059] Examples of suitable unsaturated fatty acids include, but
are not limited to, undecylenic acid, myristoleic acid, palmitoleic
acid, oleic acid, linoleic acid, alpha-linolenic acid, arachidonic
acid, eicosapentaenoic acid, erucic acid, and docosahexaenoic acid.
This series of fatty acids have tail lengths that range from 11
carbons to 24 carbons. In some embodiments, metal salts of the
fatty acids may be used in lieu of or in addition to the carboxylic
acid form.
[0060] Examples of suitable long-chain amines include, but are not
limited to, butylamine, pentylamine, hexylamine, heptylamine,
octylamine, nonylamine, decylamine, undecylamine, dodecylamine,
tridecylamine, tetradecylamine, pentadecylamine, hexadecylamine,
heptadecylamine, octadecylamine, nonadecylamine, eicosylamine,
uncosylamine acid, docosylamine acid, tricosylamine acid,
tetracosylamine, decenylamine, undecenylamine, dodecenylamine,
tridecenylamine, tetradecenylamine, pentadecenylamine,
hexadecenylamine, heptadecenylamine, octadecenylamine,
nonadecenylamine, eicocenylamine, uncocenylamine, dococenylamine,
tricocenylamine, and tetracocenylamine.
[0061] Examples of suitable surfactants include, but are not
limited to, octylphenol ethoxylates, phosphonic acids, phosphinic
acids, sulfonic acids, and polyethylene glycol monoalkyl ethers.
Example octylphenol ethoxylates include detergents of the
well-known Triton-X series. Examples of Triton-X detergents include
Triton-X 15, Triton-X 35, Triton-X 45, Triton-X 100, Triton-X 102,
Triton-X 114, Triton-X 165, Triton-X 305, Triton-X 405, and
Triton-X 705. Polyethylene glycol monoalkyl ethers have the general
formula CH.sub.3(CH.sub.2).sub.yO(CH.sub.2CH.sub.2O).sub.xH.
Example polyethylene glycol monoalkyl ethers include tetraethylene
glycol monooctyl ether, pentaethylene glycol monooctyl ether,
hexaethylene glycol monooctyl ether, pentaethylene glycol monodecyl
ether, pentaethylene glycol monodecyl ether, nonaethylene glycol
monodecyl ether, octaethylene glycol monododecyl ether,
nonaethylene glycol monododecyl ether, decaethylene glycol
monododecyl ether, octaethylene glycol monotridecyl ether, and
dodecyl glycol monodecyl ether.
[0062] Examples of suitable long-chain alcohols are organic
compounds with at least one hydroxyl functional group attached to
an aliphatic tail. The aliphatic tail may be unbranched or branched
and the aliphatic tail may be saturated or unsaturated. Examples of
long-chain alcohols include, but are not limited to, butanol,
isobutanol, pentanol, hexanol, heptanol, octanol, nonanol, decanol,
undecanol, dodecanol, tetradecanol, cetyl alcohol, stearyl alcohol,
arachidyl alcohol, docosanol, octanosol, ethyl hexanol, palmitoleyl
alcohol, stearyl alcohol, isostearyl alcohol, elaidyl alcohol,
oleyl alcohol, linoleyl alcohol, elaidolinoleyl alcohol, linolenyl
alcohol, elaidolinolenyl alcohol, ricinoleyl alcohol, arachidyl
alcohol, behenyl alcohol, erucyl alcohol, lignoceryl alcohol, ceryl
alcohol, montanyl alcohol, myricyl alcohol, lacceryl alcohol,
geddyl alcohol, 1-hexadecanol, 1-octadecanol, 1-eicosanol,
1-docosanol, 1-tetracosanol, 1-hexacosanol, 1-octacosanol,
1-triacontanol, 1-dotriacontanol, and 1-tetratriacontanol.
[0063] Additional examples of suitable surface modifiers include,
but are not limited to, cetyl pyridinium chloride, gelatin, casein,
phosphatides, dextran, glycerol, gum acacia, cholesterol,
tragacanth, stearic acid, benzalkonium chloride, calcium stearate,
glycerol monostearate, cetostearyl alcohol, cetomacrogol
emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers,
polyoxyethylene castor oils, polyoxyethylene sorbitan fatty acid
esters, polyethylene glycols, dodecyl trimethyl ammonium bromide,
polyoxyethylene stearates, colloidal silicon dioxide, phosphates,
sodium dodecylsulfate, carboxymethylcellulose calcium,
hydroxypropyl celluloses, hydroxypropyl methylcellulose,
carboxymethylcellulose sodium, methylcellulose,
hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate,
noncrystalline cellulose, magnesium aluminum silicate,
triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone,
4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and
formaldehyde, poloxamers; poloxamines, a charged phospholipid,
dioctylsulfosuccinate, dialkylesters of sodium sulfosuccinic acid,
sodium lauryl sulfate, alkyl aryl polyether sulfonates, mixtures of
sucrose stearate and sucrose distearate,
p-isononylphenoxypoly-(glycidol), decanoyl-N-methylglucamide;
n-decyl .beta.-D-glucopyranoside; n-decyl .beta.-D-maltopyranoside;
n-dodecyl .beta.-D-glucopyranoside; n-dodecyl .beta.-D-maltoside;
heptanoyl-N-methylglucamide; n-heptyl-.beta.-D-glucopyranoside;
n-heptyl .beta.-D-thioglucoside; n-hexyl .beta.-D-glucopyranoside;
nonanoyl-N-methylglucamide; n-noyl .beta.-D-glucopyranoside;
octanoyl-N-methylglucamide; n-octyl-.beta.-D-glucopyranoside; octyl
.beta.-D-thioglucopyranoside; lysozyme, PEG-derivatized
phospholipid, PEG-derivatized cholesterols, PEG-derivatized vitamin
A, PEG-derivatized vitamin E, random copolymers of vinyl acetate
and vinyl pyrrolidone, a polymer, a biopolymer, a polysaccharide, a
cellulosic, an alginate, a nonpolymeric compound, a phospholipid,
zwitterionic stabilizers, poly-n-methylpyridinium, anthryul
pyridinium chloride, chitosan, polylysine, polyvinylimidazole,
polybrene, polymethylmethacrylate trimethylammoniumbromide bromide
(PMMTMABr), hexyldesyltrimethylammonium bromide (HDMAB),
polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl
sulfate, 1,2
Dipalmitoyl-sn-Glycero-3-Phosphoethanolamine-N-[Amino(Polyethylene
Glycol)2000] (sodium salt), Poly(2-methacryloxyethyl
trimethylammonium bromide), poloxamines, lysozyme, alginic acid,
carrageenan, POLYOX, cationic lipids, sulfonium, phosphonium,
quarternary ammonium compounds, stearyltrimethylammonium chloride,
benzyl-di(2-chloroethyl)ethylammonium bromide, coconut trimethyl
ammonium chloride, coconut trimethyl ammonium bromide, coconut
methyl dihydroxyethyl ammonium chloride, coconut methyl
dihydroxyethyl ammonium bromide, decyl triethyl ammonium chloride,
decyl dimethyl hydroxyethyl ammonium chloride, decyl dimethyl
hydroxyethyl ammonium bromide, C.sub.12-15dimethyl hydroxyethyl
ammonium chloride, C.sub.12-15dimethyl hydroxyethyl ammonium
bromide, coconut dimethyl hydroxyethyl ammonium chloride, coconut
dimethyl hydroxyethyl ammonium bromide, myristyl trimethyl ammonium
methyl sulphate, lauryl dimethyl benzyl ammonium chloride, lauryl
dimethyl benzyl ammonium bromide, lauryl dimethyl(ethenoxy).sub.4
ammonium chloride, lauryl dimethyl(ethenoxy).sub.4 ammonium
bromide, N-alkyl(C.sub.12-18)dimethylbenzyl ammonium chloride,
N-alkyl(C.sub.14-18)dimethyl-benzyl ammonium chloride,
N-tetradecyldimethylbenzyl ammonium chloride monohydrate, dimethyl
didecyl ammonium chloride, N-alkyl and (C.sub.12-14)dimethyl
1-napthylmethyl ammonium chloride, trimethylammonium halide,
alkyl-trimethylammonium salts, dialkyl-dimethylammonium salts,
lauryl trimethyl ammonium chloride, ethoxylated
alkyamidoalkyldialkylammonium salt, an ethoxylated trialkyl
ammonium salt, dialkylbenzene dialkylammonium chloride,
N-didecyldimethyl ammonium chloride, N-tetradecyldimethylbenzyl
ammonium, chloride monohydrate, N-alkyl(C.sub.12-14)dimethyl
1-naphthylmethyl ammonium chloride, dodecyldimethylbenzyl ammonium
chloride, dialkyl benzenealkyl ammonium chloride, lauryl trimethyl
ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl
benzyl dimethyl ammonium bromide, C.sub.12, C.sub.15, C.sub.17
trimethyl ammonium bromides, dodecylbenzyl triethyl ammonium
chloride, poly-diallyldimethylammonium chloride, dimethyl ammonium
chlorides, alkyldimethylammonium halogenides, tricetyl methyl
ammonium chloride, decyltrimethylammonium bromide,
dodecyltriethylammonium bromide, tetradecyltrimethylammonium
bromide, methyl trioctylammonium chloride, polyquaternium 10,
tetrabutylammonium bromide, benzyl trimethylammonium bromide,
choline esters, benzalkonium chloride, stearalkonium chloride
compounds, cetyl pyridinium bromide, cetyl pyridinium chloride,
halide salts of quaternized polyoxyethylalkylamines, quaternized
ammonium salt polymers, alkyl pyridinium salts, amines, protonated
quaternary acrylamides, methylated quaternary polymers, cationic
guar, benzalkonium chloride, a carbonium compound, a phosphonium
compound, an oxonium compound, a halonium compound, a cationic
organometallic compound, a quarternary phosphorous compound, a
pyridinium compound, an anilinium compound, an ammonium compound, a
hydroxylammonium compound, a primary ammonium compound, a secondary
ammonium compound, a tertiary ammonium compound, behenalkonium
chloride, benzethonium chloride, cetylpyridinium chloride,
behentrimonium chloride, lauralkonium chloride, cetalkonium
chloride, cetrimonium bromide, cetrimonium chloride, cethylamine
hydrofluoride, chlorallylmethenamine chloride (Quaternium-15),
distearyldimonium chloride (Quaternium-5), dodecyl dimethyl
ethylbenzyl ammonium chloride (Quaternium-14), Quaternium-22,
Quaternium-26, Quaternium-18 hectorite, dimethylaminoethylchloride
hydrochloride, cysteine hydrochloride, diethanolammonium POE (10)
oletyl ether phosphate, diethanolammonium POE (3) oleyl ether
phosphate, tallow alkonium chloride, dimethyl
dioctadecylammoniumbentonite, stearalkonium chloride, domiphen
bromide, denatonium benzoate, myristalkonium chloride,
laurtrimonium chloride, ethylenediamine dihydrochloride, guanidine
hydrochloride, pyridoxine HCl, iofetamine hydrochloride, meglumine
hydrochloride, methylbenzethonium chloride, myrtrimonium bromide,
oleyltrimonium chloride, polyquaternium-1, procainehydrochloride,
cocobetaine, stearalkonium bentonite, stearalkoniumhectonite,
stearyl trihydroxyethyl propylenediamine dihydrofluoride,
tallowtrimonium chloride, and hexadecyltrimethyl ammonium
bromide.
III. Manufacturing Stable Nanoparticulate Vitamin Compositions
[0064] The stable nanoparticulate vitamin compositions are prepared
via a method that may include one or more steps such as, but not
limited to, (1) selecting at least one vitamin compound, (2)
providing a precursor mixture that includes particles of the at
least one vitamin compound, at least one solvent in which the at
least one vitamin compound has a solubility of less than 10 mg/ml,
and a surface modifying agent that is dispersible in the at least
one solvent and is capable of stably associating with the particles
of the at least one vitamin compound, and (3) treating the
precursor mixture to produce the stable nanoparticulate vitamin
composition, wherein the stable nanoparticulate vitamin composition
includes smaller sized vitamin particles (e.g., than is the
precursor mixture) having a coating of surface modifying agent.
[0065] In the treating step of the method the vitamin particles are
broken down to form a stable nanoparticulate vitamin composition.
In practice, the treating step is carried out using, e.g., a
microfluidizer and/or a sonicator.
A. The Microfluidizer
[0066] The primary forces attributed to microfluidization by the
microfluidizer for producing either emulsions or dispersions, and
for reducing mean particle size include, but are not limited
to:
[0067] shear, involving boundary layers, turbulent flow,
acceleration and change in flow direction;
[0068] impact, involving collision of the particles processed with
solid elements of the microfluidizer, and collision between the
particles being processed; and
[0069] cavitation, involving an increased change in velocity with a
decreased change in pressure, and turbulent flow.
[0070] An additional force can be attributed to attrition, i.e.,
grinding by friction.
[0071] A typical microfluidizer consists of an air motor connected
to a hydraulic pump which circulates the process fluid. The
formulation stream is propelled at high pressures (up to e.g.
23,000 psi) through a specially designed interaction chamber which
has fixed microchannels that focus the formulation stream and
accelerate it to a high velocity. Within the chamber the
formulation is subjected to intense shear, impact and cavitation,
all of which contribute to particle size reduction. After
processing, the formulation stream is passed through a heat
exchanger coil and can be collected or recirculated through the
machine. A microfluidizer is typically used in a continuous
processing mode for up to three hour of total processing time. The
heat exchanger and interaction chamber are externally cooled with a
refrigerated circulating water bath.
B. Sonication
[0072] Sonication acts to break down the vitamin particles in the
precursor mixture to smaller particles primarily through inducing
high velocity interparticle collisions in the slurry and through
the formation of microbubbles that generate violent shockwaves and
microjets when the bubbles collapse. The force of interparticle
collisions is a function of solvent type and the intensity of the
sonic energy that is transmitted into the slurry. Bubble collapse
and the forces generated therein are a function of the solvent type
and the temperature of the solvent during sonication. Briefly
stated, the forces generated by bubble collapse are greatest if the
vapor pressure of the solvent inside the bubble is minimized. Vapor
pressure is a function of solvent type and temperature. As such, it
can be advantageous to sonicate at a temperature in a range from
about 0.degree. C. to about 60.degree. C., or in a range from about
1.degree. C. to about 40.degree. C., or in a range from about
2.degree. C. to about 20.degree. C., or in a range from about
5.degree. C. to about 10.degree. C.
C. The Process of Making the Nanoparticulates
[0073] Regardless of the procedure utilized, e.g.,
microfluidization or sonication or a blend of the two, the coarse
vitamin substance is selected and added to a liquid medium in which
it is essentially insoluble to form a premix. The concentration of
the vitamin substance in the liquid medium can range from about 0.1
wt % to about 60 wt %. It is typical, but not essential, that the
surface modifier be present in the premix. In some embodiments,
concentration of the vitamin substance in the liquid medium can
range from about 0.1 wt %, 0.2 wt %, 0.5 wt %, 1 wt %, 5 wt %, 10
wt %, 15 wt %, 20 wt %, 25 wt %, 30 wt %, 35 wt %, 40 wt %, 45 wt
%, 50 wt %, 55 wt %, or about 60 wt %.
[0074] The concentration of the surface modifier can vary from
about 0.1 to 90%, or from about 1-75%, or from about 20-60%, by
weight based on the total combined weight of the vitamin substance
and surface modifier. In some embodiments, the concentration of the
surface modifier can vary from about 0.1%, 0.2%, 0.5%, 1%, 5%, 10%,
15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%,
80%, 85%, or 90%, to about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%,
40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%, or to about 20%, 25%,
30%, 35%, 40%, 45%, 50%, 55%, or 60%.
[0075] The relative amount of vitamin substance and surface
modifier can vary widely and the optimal amount of the surface
modifier can depend, for example, upon the particular vitamin
substance and surface modifier selected, the critical micelle
concentration of the surface modifier if it forms micelles,
etc.
[0076] The premix can be circulated in a microfluidizer
continuously first at low pressures, then at maximum capacity
having a fluid pressure of from about 3,000 to 30,000 psi until the
desired particle size reduction is achieved. The particles should
be reduced in size at a temperature which does not significantly
degrade the vitamin substance. Processing temperatures in a range
from about 0.degree. C. to about 60.degree. C. are typical.
Processing temperature in a range from about 1.degree. C. to about
40.degree. C., or in a range from about 2.degree. C. to about
20.degree. C., or in a range from about 5.degree. C. to about
10.degree. C. can also be usefully employed.
[0077] There are at least two methods to collect a slurry and
re-pass it in a microfluidizer. The "discreet pass" method collects
every pass through the microfluidizer until all of the slurry has
been passed through before re-introducing it again to the
microfluidizer. This guarantees that every substance or particle
has "seen" the interaction chamber the same amount of times. A
second method recirculates the slurry by collecting it in a
receiving tank and allowing the entire mixture to randomly mix and
pass through the interaction chamber. We have found that
recirculating a slurry is just as effective as the "discreet pass"
method, however, maintaining slurry homogeneity in the receiving
tank is important.
[0078] In the case of sonication, the precursor mixture is
sonicated for a period of time sufficient to break down the vitamin
particles in the precursor mixture to nano-scale particles. In one
embodiment, the precursor mixture is sonicated for a time between
about 5 minutes and about 2 hours. In another embodiment, the
precursor mixture is sonicated for a time between about 10 minutes
and about 1 hour. In still another embodiment, the precursor
mixture is sonicated to for a time between about 15 minutes and
about 30 minutes. In some embodiments, the precursor mixture is
sonicated for about 5 minutes, 10 minutes, 15 minutes, 20 minutes,
25, minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50
minutes, 55 minutes, 60 minutes, 90 minutes, or 120 minutes, or
about 10 minutes, 15 minutes, 20 minutes, 25, minutes, 30 minutes,
35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, or 60
minutes, or about 15 minutes, 20 minutes, 25, minutes, or 30
minutes.
[0079] As mentioned above, sonication is typically conducted at a
low temperature in order to minimize the vapor pressure of the
solvent. In this case, it is also advantageous to sonicate at a low
temperature to avoid degrading the vitamin substance. As such, it
can be advantageous to sonicate at a temperature in a range from
about 0.degree. C. to about 60.degree. C., or in a range from about
1.degree. C. to about 40.degree. C., or in a range from about
2.degree. C. to about 20.degree. C., or in a range from about
5.degree. C. to about 10.degree. C.
[0080] In one embodiment, the sonicator transmits sonic energy into
the precursor mixture in a sequence of pulses. For example, a
typical sonication procedure sonication procedure calls for a pulse
sequence of 5 seconds on/2 seconds off. If, for example, the sample
is sonicated for a total of 21 minutes, during 15 minutes of that
time the sample is undergoing active sonication.
[0081] The resulting nanoparticulate vitamin composition is stable
and includes the liquid dispersion medium and the above-described
particles. In some embodiments, the stabilized vitamin particles
can be used to supplement dietary vitamin content in a number ways.
For example, the dispersed particles can be directly combined with
a number of foods including, but not limited to, water-based
beverages, processed meat products, processed fish products, gels
such as energy gels, jams, pastes, nutrition bars, bakery products,
creams, sauces, dairy products, confections, or syrups, and
combinations thereof.
[0082] In some embodiments, the stabilized vitamin particles can be
purified from the solvent and used to supplement dietary vitamin
content. For example, the stabilized vitamin particles can be
purified from the solvent by filtration, centrifugation or by
vitamin spray coating them onto sugar spheres or onto any one of
the pharmaceutical excipients discussed above using, for example, a
fluid-bed spray coater by techniques well known in the art.
Purified nanoparticles can be directly combined with a number of
foods including, but not limited to, pet foods, water-based
beverages, processed meat products, processed fish products, gels
such as energy gels, jams, pastes, nutrition bars, bakery products,
creams, sauces, dairy products, confections, or syrups, and
combinations thereof. In addition, the purified particles can be
inserted into capsules or pressed into pills, caplets, or tablets
and be used as vitamin supplements.
[0083] The stable nanoparticulate vitamin compositions may be
embodied in other specific forms without departing from the spirit
or essential characteristics of this disclosure. The described
embodiments are to be considered in all respects only as
illustrative and not restrictive. All changes that come within the
meaning and range of equivalency of the claims are to be embraced
within their scope.
[0084] The present disclosure is not to be limited in terms of the
particular embodiments described in this application, which are
intended as illustrations of various aspects. Many modifications
and variations can be made without departing from its spirit and
scope, as will be apparent to those skilled in the art.
Functionally equivalent methods and apparatuses within the scope of
the disclosure, in addition to those enumerated herein, will be
apparent to those skilled in the art from the foregoing
descriptions. Such modifications and variations are intended to
fall within the scope of the appended claims. The present
disclosure is to be limited only by the terms of the appended
claims, along with the full scope of equivalents to which such
claims are entitled. It is to be understood that this disclosure is
not limited to particular methods, reagents, compounds compositions
or biological systems, which can, of course, vary. It is also to be
understood that the terminology used herein is for the purpose of
describing particular embodiments only, and is not intended to be
limiting.
[0085] With respect to the use of substantially any plural and/or
singular terms herein, those having skill in the art can translate
from the plural to the singular and/or from the singular to the
plural as is appropriate to the context and/or application. The
various singular/plural permutations may be expressly set forth
herein for sake of clarity.
[0086] It will be understood by those within the art that, in
general, terms used herein, and especially in the appended claims
(e.g., bodies of the appended claims) are generally intended as
"open" terms (e.g., the term "including" should be interpreted as
"including but not limited to," the term "having" should be
interpreted as "having at least," the term "includes" should be
interpreted as "includes but is not limited to," etc.). It will be
further understood by those within the art that if a specific
number of an introduced claim recitation is intended, such an
intent will be explicitly recited in the claim, and in the absence
of such recitation no such intent is present. For example, as an
aid to understanding, the following appended claims may contain
usage of the introductory phrases "at least one" and "one or more"
to introduce claim recitations. However, the use of such phrases
should not be construed to imply that the introduction of a claim
recitation by the indefinite articles "a" or "an" limits any
particular claim containing such introduced claim recitation to
embodiments containing only one such recitation, even when the same
claim includes the introductory phrases "one or more" or "at least
one" and indefinite articles such as "a" or "an" (e.g., "a" and/or
"an" should be interpreted to mean "at least one" or "one or
more"); the same holds true for the use of definite articles used
to introduce claim recitations. In addition, even if a specific
number of an introduced claim recitation is explicitly recited,
those skilled in the art will recognize that such recitation should
be interpreted to mean at least the recited number (e.g., the bare
recitation of "two recitations," without other modifiers, means at
least two recitations, or two or more recitations). Furthermore, in
those instances where a convention analogous to "at least one of A,
B, and C, etc." is used, in general such a construction is intended
in the sense one having skill in the art would understand the
convention (e.g., "a system having at least one of A, B, and C"
would include but not be limited to systems that have A alone, B
alone, C alone, A and B together, A and C together, B and C
together, and/or A, B, and C together, etc.). In those instances
where a convention analogous to "at least one of A, B, or C, etc."
is used, in general such a construction is intended in the sense
one having skill in the art would understand the convention (e.g.,
"a system having at least one of A, B, or C" would include but not
be limited to systems that have A alone, B alone, C alone, A and B
together, A and C together, B and C together, and/or A, B, and C
together, etc.). It will be further understood by those within the
art that virtually any disjunctive word and/or phrase presenting
two or more alternative terms, whether in the description, claims,
or drawings, should be understood to contemplate the possibilities
of including one of the terms, either of the terms, or both terms.
For example, the phrase "A or B" will be understood to include the
possibilities of "A" or "B" or "A and B."
[0087] In addition, where features or aspects of the disclosure are
described in terms of Markush groups, those skilled in the art will
recognize that the disclosure is also thereby described in terms of
any individual member or subgroup of members of the Markush
group.
[0088] As will be understood by one skilled in the art, for any and
all purposes, such as in terms of providing a written description,
all ranges disclosed herein also encompass any and all possible
subranges and combinations of subranges thereof. Any listed range
can be easily recognized as sufficiently describing and enabling
the same range being broken down into at least equal halves,
thirds, quarters, fifths, tenths, etc. As a non-limiting example,
each range discussed herein can be readily broken down into a lower
third, middle third and upper third, etc. As will also be
understood by one skilled in the art all language such as "up to,"
"at least," "greater than," "less than," and the like include the
number recited and refer to ranges which can be subsequently broken
down into subranges as discussed above. Finally, as will be
understood by one skilled in the art, a range includes each
individual member. Thus, for example, a group having 1-3 cells
refers to groups having 1, 2, or 3 cells. Similarly, a group having
1-5 cells refers to groups having 1, 2, 3, 4, or 5 cells, and so
forth."
[0089] While various aspects and embodiments have been disclosed
herein, other aspects and embodiments will be apparent to those
skilled in the art. The various aspects and embodiments disclosed
herein are for purposes of illustration and are not intended to be
limiting, with the true scope and spirit being indicated by the
following claims.
* * * * *